The excitotoxic effects of kainic acid, AMPA and N-methyl-D-aspartate were studied in mesencephalic primary cultures. Dopaminergic neurons, comprising about 5 % of the total cell population, are more vulnerable to glutamate receptor stimulation than calretinin-containing neurons. A 24 h exposure to 500 mu M kainic acid reduced the number of dopamine-containing neurons by 40 % but failed to change that of calretinin-containing neurons. The latter neuronal subtype is injuried by 48 h continuous exposure to kainic acid. Immunohistochemical studies showed that the GluR2/R3 receptor subtype was present in both cell types ruling out a difference in receptor subtype expression. In addition, both neuronal subtypes responded to GluR2/R3 receptor stimulation, because phosphorylated cAMP/Ca2+ response element-binding protein levels are increased in both cell types.The present results support the inference that calretinin may play a [Ca2+]i -buffering role that conferes resistance to glutamate neurotoxicity.